TY - JOUR
T1 - Biphenylquinuclidines as inhibitors of squalene synthase and growth of parasitic protozoa
AU - Lorente, Silvia Orenes
AU - Gomez, Rosario
AU - Jimenez, Carmen
AU - Cammerer, Simon
AU - Yardley, Vanessa
AU - de Luca-Fradley, Kate
AU - Croft, Simon L.
AU - Perez, Luis M. Ruiz
AU - Urbina, Julio
AU - Pacanowska, Dolores Gonzalez
AU - Gilbert, Ian H.
PY - 2005/5/16
Y1 - 2005/5/16
N2 - In this paper we describe the preparation of some biphenylquinuclidine derivatives and their evaluation as inhibitors of squalene synthase in order to explore their potential in the treatment of the parasitic diseases leishmaniasis and Chagas disease. The compounds were screened against recombinant Leishmania major squalene synthase and against Leishmania mexicana promastigotes, Leishmania donovani intracellular amastigotes and Trypanosoma cruzi intracellular amastigotes. Compounds that inhibited the enzyme, also reduced the levels of steroids and caused growth inhibition of L. mexicana promastigotes. However there was a lower correlation between inhibition of the enzyme and growth inhibition of the intracellular parasites, possibly due to delivery problems. Some compounds also showed growth inhibition of T brucei rhodesiense trypomastigotes, although in this case alternative modes of action other than inhibition of SQS are probably involved.
AB - In this paper we describe the preparation of some biphenylquinuclidine derivatives and their evaluation as inhibitors of squalene synthase in order to explore their potential in the treatment of the parasitic diseases leishmaniasis and Chagas disease. The compounds were screened against recombinant Leishmania major squalene synthase and against Leishmania mexicana promastigotes, Leishmania donovani intracellular amastigotes and Trypanosoma cruzi intracellular amastigotes. Compounds that inhibited the enzyme, also reduced the levels of steroids and caused growth inhibition of L. mexicana promastigotes. However there was a lower correlation between inhibition of the enzyme and growth inhibition of the intracellular parasites, possibly due to delivery problems. Some compounds also showed growth inhibition of T brucei rhodesiense trypomastigotes, although in this case alternative modes of action other than inhibition of SQS are probably involved.
U2 - 10.1016/j.bmc.2005.02.060
DO - 10.1016/j.bmc.2005.02.060
M3 - Article
SN - 0968-0896
VL - 13
SP - 3519
EP - 3529
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 10
ER -